Insulin resistance and glucose intolerance have classically been associated with aging in humans. Recent studies, however, suggest that lifestyle, as opposed to aging per se, might be responsible for the development of insulin resistance in older individuals. Insulin resistance and the resultant hyperinsulinemia are risk factors for non-insulin-dependent diabetes mellitus and atherosclerosis. More recently, insulin resistance has been implicated as a major factor in a metabolic syndrome consisting of hyperinsulinemia, hypertension, obesity, hypertriglyceridemia and increased blood clotting, all risk factors for atherosclerosis. The long-term objectives of this continuation proposal are to better understand the mechanisms involved in regulating glucose transport in skeletal muscle, the major insulin-responsive tissue in the body. Using the Fischer 344 rat, the investigators have previously shown that insulin resistance does not develop when rats are raised on a low-fat, high-complex-carbohydrate (LFCC) diet. However, when rats were raised on a high-fat, refined sugar (HFS) diet, insulin resistance was well developed at 2 yr of age. In addition, the HFS rats become obese, hypertensive, hypertriglyceridemic and had increased blood clotting compared to the LFCC rats. The specific aims of this proposal are to investigate the mechanisms by which the HFS diet induces skeletal muscle insulin resistance and how the resultant hyperinsulinemia induces obesity and hypertension. Fischer 344 rats will be raised for up to 2 years on either the HFS or LFCC diet. Studies on insulin resistance in skeletal muscle will focus on insulin receptor autophosphorylation and tyrosine kinase activity. Studies on obesity will focus on the effects of hyperinsulinemia on lipoprotein and hormone- sensitive lipase in fat cells as well as hypothalamic regulation of food intake. Studies on hypertension will focus on the role that insulin exerts via the autonomic nervous system. The results of this project should provide important insight into the role that diet plays in the induction of insulin resistance, obesity and hypertension, all major health problems in this country.